ASCO 2014 - Abstract LBA1

ASCO 2014. Abstract LBA1. Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials.

Olivia Pagani, Meredith M. Regan, Barbara Walley, Gini F. Fleming, Marco Colleoni, Istvan Lang, Henry Leonidas Gomez, Carlo Tondini, Harold J. Burstein, Edith A. Perez, Eva Ciruelos, Vered Stearns, Herve R. Bonnefoi, Silvana Martino, Charles E. Geyer, Manuela Rabaglio-Poretti, Alan S. Coates, Richard D. Gelber, Aron Goldhirsch, Prudence A. Francis, SOFT and TEXT Investigators and International Breast Cancer Study Group; Institute of Oncology of Southern Switzerland, SAKK & IBCSG, Lugano Viganello, Switzerland; IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA; NCIC Clinical Trials Group, Kingston, ON, Canada; The University of Chicago Medical Center & Alliance, Chicago, IL; European Institute of Oncology & IBCSG, Milan, Italy; National Institute of Oncology, Budapest, Hungary; Instituto Nacional de Enfermedades Neoplásicas & IBCSG, Lima, Peru; Osp. Papa Giovanni XXIII, Bergamo, Italy; Dana-Farber Cancer Institute & Alliance, Boston, MA; Mayo Clinic & Alliance, Jacksonville, FL; University Hospital 12 de Octubre, Madrid, Spain; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and ECOG, Baltimore, MD; Bergonié Institute & EORTC, Bordeaux, France; The Angeles Clinic and Research Institute & SWOG, Santa Monica, CA; Massey Cancer Center, Virginia Commonwealth University School of Medicine & NRG Oncology, Richmond, VA; Institute of Medical Oncology & International Breast Cancer Study Group, Berne, Switzerland; International Breast Cancer Study Group, Berne, Switzerland; Peter MacCallum Cancer Center, ANZBCTG, Melbourne, Australia

Background: Adjuvant endocrine therapy with AI vs T improves outcomes in postmenopausal HR+ BC. TEXT and SOFT were designed to test whether adjuvant AI improves outcomes in premenopausal women with HR+ BC treated with OFS (AI question) and to determine the value of OFS in women who remain premenopausal and are suitable for adjuvant T (OFS question). 

Methods: TEXT and SOFT, randomized phase 3 trials, enrolled 5,738 premenopausal women with HR+ early BC from Nov03 to Apr11 (2672 TEXT; 3066 SOFT). TEXT randomized women within 12wk of surgery to 5y E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5y E+OFS vs T+OFS vs T alone, either within 12wk of surgery if no CT planned, or within 8mo of completing (neo)adjuvant CT. OFS was by choice of 5y triptorelin, oophorectomy, or ovarian irradiation. The primary endpoint is disease-free survival (DFS: randomization until invasive local, regional, distant recurrence, or contralateral breast; 2nd malignancy; death). Due to low event rates, protocol amendments in 2011 changed the analysis plans to answer the AI question (E+OFS vs T+OFS) by joint analysis of TEXT and SOFT. By Q3’2013 with >5y median follow-up, 436 DFS events were projected, providing 84% power for HR=0.75 with E+OFS vs T+OFS (stratified log rank 2-sided α=0.05). 

Results: At 5.7y median follow-up, 514 (11%) DFS events were reported in the ITT population comparing E+OFS (n=2346) vs T+OFS (n=2344). Patients assigned E+OFS had significantly reduced DFS hazard (HR=0.72; 95% CI, 0.60-0.86; P=0.0002) vs T+OFS; 5y DFS was 91.1% vs 87.3%. Reductions were similar for secondary endpoints of BC-free interval (HR=0.66 (0.55-0.80) 5y BCFI 92.8% vs 88.8%) and distant recurrence-free interval (HR=0.78 (0.62-0.97)), though not overall survival (HR=1.14 (0.86-1.51)) at this early follow-up (194 (4%) deaths). Grade 3-4 targeted AEs were reported in 31% E+OFS vs 29% T+OFS patients. 

Conclusion: In premenopausal women with HR+ BC, adjuvant treatment with E+OFS significantly reduced the risk of recurrence compared to T+OFS. 

• The combined analysis of these two large RCTs of ovarian suppression in pre-menopausal women with early stage ER+ breast cancer comparing an aromatase inhibitor (AI) versus tamoxifen parallels the results seen in post-menopausal women trials (BIG 1-98 and ATAC) of improvements in DFS in favor of the AI over tamoxifen without a clear improvement in Overall Survival to date1.

• These results are contrary to the results of the ABCSG-12 trial2. Though reconciliation as to the specific reasons is needed – possible explanations include the duration of OFS + hormonal therapy (3 years vs 5 years) and selection of a population of patients with a better prognosis and perhaps more sensitive overall to any hormonal manipulation in the ABCSG-12 study.

• The side effect profiles are different across the two regimens, with a greater discontinuation rate for the OFS + exemestane arms, but an adverse event profile consistent with AIs in post-menopausal women (more musculoskeletal symptoms, decreased bone density, vaginal dryness and dyspareunia) and no difference in QOL as measured in the trials.

• The lack of results from the tamoxifen only arm (in SOFT) precludes direct comparison to the general standard of care of today, which is tamoxifen alone in the majority of such patients.

• These results do suggest that ovarian function suppression with exemestane is an option for pre-menopausal women with early stage ER+ breast cancer, particularly those intolerant to or with a contra-indication to tamoxifen

• Wide spread publicly funded adoption of this therapeutic strategy (OFS + exemestane) would benefit from the identification of the subset of patients that derive the greatest benefit to this treatment strategy, a survival signal benefit, knowledge of the results of tamoxifen alone as a therapeutic strategy (forthcoming from SOFT), and a well performed cost-effective analysis.
— The CARE Breast Cancer Faculty


  1. Pagani O, Regan M, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med published online June 1, 2014 at
  2. Gnant M. Mlineritsch B, Stoeger H, et al. Adjuvant endocrine therapy plus zolendronic acid in premenopausal women with early stage breast cancer: 62 months follow up from the ABCSG-12 randomised trial. Lancet Oncol 2011;12:631-41.